The proposed multidisciplinary study will examine the clinical, virologic and immunologic characteristics of acute hepatitis C virus (HCV) infection among street-recruited injection drug users (IDUs). A cohort of 100 HCV-uninfected IDUs will be followed prospectively. A highly sensitive transcription-mediated-amplification (TMA) assay will be used to detect HCV RNA in biweekly plasma specimens. Based on the HCV incidence rates we have observed in the study community, we estimate that we will observe as many as 70 new infections. Clinical, virologic, and immunologic studies of these infections will be conducted in concert, to characterize primary HCV infections among IDUs, and to assess clinical, immunologic, and virologic characteristics associated with successful immune responses and viral clearance, The aims of the proposed study are to: (1) describe the natural history of acute HCV infection in street-recruited, active IDUs by prospectively observing the spectrum of clinical and laboratory features, the viral kinetics of early infection, the proportion who spontaneously clear infection, and the timing of clearance; (2) characterize the evolution of HCV-specific cellular immune responses in acute HCV infection, including the HCV epitope specificity, precursor frequency, phenotype, cytokine profile, proliferation and cytotoxicity of HCV-specific T-cells; and (3) study the kinetics and function of HCV-specific cellular immune responses in parallel with the virologic events, comparing IDUs whose infection is cleared with those who progress to chronic infection, to determine the characteristics of a successful immune response to HCV.